The pathogenesis of asthma results from interactions between the innate (Project 1) and adaptive (Project 3)[unreadable] immune systems. A subset of immune cells, regulatory CD4+ T cells, play an important role in suppression[unreadable] of both innate and adaptive responses. Although there are indications that regulatory T cells participate in[unreadable] asthma, much remains to be learned before therapeutic interventions can be entertained. The goal of the[unreadable] first part of this Project is to better define the role of complement regulator (CD46) activated human T cells,[unreadable] which appear to represent a unique adaptive regulatory T cell subset. In Aim 1, we will determine if[unreadable] complement activation plays an important role in asthma, as well as providing a physiologic in vivo stimulus[unreadable] for these adaptive regulatory T cells. We will ask if genetic deficiency in various complement components[unreadable] (beginning with C3) modulates the Sendai virus-induced acute infection and the chronic asthma phenotype[unreadable] in mice (as described in Project 1). We will also determine whether markers of altered complement activation[unreadable] occur in situ in human patients with asthma. In Aim 2, we will look for the presence of T cells with the CD46[unreadable] adaptive regulatory T cell phenotype in human patients with asthma. We will also determine if human CD46[unreadable] adaptive regulatory T cells inhibit the function of pathogenic cells in asthma (Th2 cells and B cells). If so, this[unreadable] would argue for further studies into the use of these adaptive regulatory cells for the treatment of asthma. In[unreadable] the second part of this Project, we will complement the above studies on adaptive regulatory T cells and[unreadable] define the role of natural regulatory T cells in a mouse model of asthma. By moving to this model, we can[unreadable] utilize a newly described marker Foxp3-GFP for natural regulatory T cells to facilitate studies of natural[unreadable] regulatory T cell specificity. In summary, our goal is to further address the role of the complement system in[unreadable] asthma and whether adaptive or natural regulatory T cells participate in controlling the severity of asthma.[unreadable] Both avenues represent attractive therapeutic targets for the treatment of asthma. Asthma is a growing[unreadable] problem in the United States, but current therapies are expensive, chronic, and, unfortunately not curative.[unreadable] By exploring the body's innate immune system and natural regulatory mechanisms that inhibit excessive[unreadable] pathology, our hope is that curative therapies can eventually be generated not requiring global[unreadable] immunosuppression.